Capivasertib (AZD5363)
Class
- Oral AKT (Protein Kinase B) inhibitor
- Targeted therapy acting on the PI3K–AKT–mTOR pathway
Mechanism of Action
- Capivasertib is a potent, selective inhibitor of AKT isoforms (AKT1, AKT2, AKT3).
- It blocks AKT phosphorylation and downstream signaling, leading to:
- ↓ tumor cell proliferation
- ↑ apoptosis
- ↓ cell survival and metabolism
- Particularly effective in tumors with PI3K/AKT pathway–activating alterations, where AKT signaling drives oncogenesis.
Approved / Key Clinical Indication
HR-positive, HER2-negative advanced or metastatic breast cancer, in combination with fulvestrant, in patients with:
- PIK3CA
- AKT1
- PTEN alterations
Approval is based largely on CAPItello-291, which showed improved PFS in biomarker-selected patients.
Biomarker Considerations (Critical for Pharmacists)
- Requires molecular testing
- Most benefit seen in tumors with:
- PIK3CA mutations
- AKT1 E17K mutation
- PTEN loss or inactivation
- Less benefit in biomarker-negative populations
Dosing & Administration
- Capivasertib:
- 400 mg orally twice daily
- 4 days on / 3 days off (intermittent dosing reduces toxicity)
- Fulvestrant:
- 500 mg IM on days 1, 15, 29, then monthly
Pharmacist note: intermittent dosing is essential—do not convert to continuous dosing.
Pharmacokinetics (High-Yield)
- Route: Oral
- Metabolism: Primarily CYP3A4
- Half-life: ~9–12 hours
- Drug–drug interactions:
- Avoid strong CYP3A4 inhibitors or inducers
- Monitor with moderate inhibitors (dose adjustment may be required)
Adverse Effects & Monitoring
Common
- Diarrhea (very common, often early)
- Rash (maculopapular, acneiform)
- Hyperglycemia (AKT inhibition → insulin signaling disruption)
- Nausea, fatigue, stomatitis
Serious / Clinically Relevant
- Grade ≥3 diarrhea
- Severe cutaneous reactions (rare)
- Persistent hyperglycemia
Monitoring Parameters
- Fasting glucose & HbA1c (baseline and periodically)
- Electrolytes (with diarrhea)
- Skin toxicity assessment
- Adherence to intermittent schedule
Dose Modifications (General Principles)
- Diarrhea: Early antidiarrheal use (e.g., loperamide); hold/reduce for ≥Grade 3
- Hyperglycemia: Initiate antihyperglycemics if needed; hold for severe cases
- Rash: Topical steroids ± oral antihistamines; dose interruption if severe
Place in Therapy
- Competes with / complements other endocrine + targeted strategies:
- Advantage over PI3K inhibitors:
- Broader activity across PI3K/AKT/PTEN alterations
- Different toxicity profile (less severe rash than alpelisib, but more diarrhea)
Key Counseling Points (Pharmacist-Led)
- Strict adherence to 4-days-on / 3-days-off schedule
- Early reporting of diarrhea or rash
- Monitor blood sugar even in non-diabetic patients
- Avoid grapefruit and CYP3A4-interacting drugs
Bottom Line
Capivasertib is a biomarker-driven AKT inhibitor that restores endocrine sensitivity in HR+/HER2– breast cancer by targeting aberrant PI3K–AKT signaling. Pharmacists play a critical role in molecular selection, toxicity prevention, drug interaction management, and adherence to its unique intermittent dosing schedule.